Our long-term goal is to elucidate the role of protein synthesis and turnover in aging. We are particularly interested in the role of protein turnover in the molecular mechanism(s) responsible for the anti-aging effect of caloric restriction. We have identified a novel protein kinase, elongation factor-2 (eEF-2) kinase, that can modulate the rate of protein synthesis in animal cells (Ryazanov et. al., (1988) Nature 334: 170-173; Ryazanov et al., (1997) Proc. Natl. Acad. Sci. 94: 4884-4889). We found that a knockout of eEF-2 kinase in Caenorhabditis elegans results in an increase in protein turnover, and extends life span. Conversely, overexpression of eEF-2 kinase in transgenic nematodes shortens life span. It has long been discussed that protein synthesis and turnover can play a causative role in aging. Our results provide the first direct experimental support of this hypothesis. From our preliminary experiments, we suggest that inactivation of eEF-2 kinase and the resulting increase in protein synthesis and degradation leads to a more efficient removal of oxidatively damaged proteins, and thus extends life span. In addition, up- regulation of protein synthesis through inhibition of eEF-2 kinase may contribute to the anti-aging effect of caloric restriction. In this grant application, we will use both C. elegans and mice as model systems. We plan to elucidate the molecular mechanism of protein synthesis inhibition during aging and to investigate the role of eEF-2 kinase and protein turnover in the anti-aging effect of caloric restriction. We will also analyze the rote of eEF-2 kinase in normal senescence and caloric restriction in mammals using the eEF-2 kinase knockout mice we recently obtained. The experiments described in this grant application are designed to provide a foundation for the development of novel therapeutic reagents that can mimic caloric restriction, circumventing some of the deleterious consequences of aging.